The present invention relates to cinnamoylaminoalkyl-substituted benzenesulfonamide derivatives of formula I 
in which A(1), A(2), A(3), R(1), R(2), R(3), R(4), X, Y, and Z have the meanings indicated below. Compounds of formula I are valuable pharmaceutical active compounds which exhibit, for example, an inhibitory action on ATP-sensitive potassium channels in the cardiac muscle and/or in the cardiac nerve and are suitable, for example, for the treatment of disorders of the cardiovascular system such as coronary heart disease, arrhythmias, cardiac insufficiency, or cardiomyopathies, or for the prevention of sudden cardiac death or for improving decreased contractility of the heart. The invention furthermore relates to processes for the preparation of compounds of formula I, their use, and pharmaceutical preparations comprising them.
A hypoglycemic action is described for certain benzenesulfonylureas. Glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus, counts as a prototype of hypoglycemic sulfonylureas of this type. Glibenclamide blocks ATP-sensitive potassium channels and is used in research as a tool for the exploration of potassium channels of this type. In addition to its hypoglycemic action, glibenclamide additionally possesses other actions that are attributed to the blockade of precisely these ATP-sensitive potassium channels, which as yet, however, still cannot be utilized therapeutically. These include, in particular, an antifibrillatory action on the heart. In the treatment of ventricular fibrillation or its early stages with glibenclamide, however, the marked hypoglycemia simultaneously produced by this substance would be undesirable or even dangerous, as it can further worsen the condition of the patient.
Various patent applications, for example U.S. Pat. No. 5,698,596, U.S. Pat. No. 5,476,850, or U.S. Pat. No. 5,652,268 and WO-A-00/03978 (German Patent Application 19832009.4), disclose antifibrillatory benzenesulfonylureas and -thioureas having decreased hypoglycemic action. WO-A-00/15204 (German Patent Application 19841534.6) describes the action of some of these compounds on the autonomic nervous system. The properties of these compounds, however, are not satisfactory in various respects, and there furthermore exists a need for compounds having a more favorable pharmacodynamic and pharmacokinetic property profile, which are better suited, in particular, to the treatment of a disturbed heart rhythm and its consequences. Various benzenesulfonylureas having an acylaminoalkyl substituent in which the acyl group can also be derived, inter alia, from cinnamic acids, are disclosed in German Laid-Open Specifications DE-A-1443878, DE-A-1518816, DE-A-1518877, and DE-A-1545810. These compounds have a hypoglycemic action, but an action on the heart is not known as yet. Surprisingly, it has now been found that certain cinnamoylaminoalkyl-substituted benzenesulfonamide derivatives are distinguished by a marked action on ATP-sensitive potassium channels in the heart and further advantageous pharmacological actions.
One subject of the present invention are compounds of formula I 
in which:
X is oxygen, sulfur, or cyanoimino;
Y is xe2x80x94(CR(5)2)nxe2x80x94;
Z is NH or oxygen;
the residues A(1), A(2), and A(3), which are independent of one another and can be identical or different, are hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, formyl, or trifluoromethyl;
R(1) is
a) (C1-C4)-alkyl;
b) xe2x80x94Oxe2x80x94(C1-C4)-alkyl;
c) xe2x80x94Oxe2x80x94(C1-C4)-alkylxe2x80x94E(1)xe2x80x94(C1-C4)-alkyl-D(1), in which D(1) is hydrogen or xe2x80x94E(2)xe2x80x94(C1-C4)-alkyl-D(2), in which D(2) is hydrogen or xe2x80x94E(3)xe2x80x94(C1-C4)-alkyl, where E(1), E(2), and E(3), which are independent of one another and can be identical or different, are O, S, or NH;
d) xe2x80x94Oxe2x80x94(C1-C4)-alkyl which is substituted by a residue of a saturated 4-membered to 7-membered heterocycle which contains one or two oxygens as ring heteroatoms;
e) xe2x80x94Oxe2x80x94(C2-C4)-alkenyl;
f) xe2x80x94Oxe2x80x94(C1-C4)-alkyl-phenyl in which the phenyl group is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl;
g) xe2x80x94O-phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl;
h) halogen;
i) phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, xe2x80x94S(O)mxe2x80x94(C1-C4)-alkyl, phenyl, amino, hydroxy, nitro, trifluoromethyl, cyano, hydroxycarbonyl, carbamoyl, (C1-C4)-alkoxycarbonyl, and formyl;
j) (C2-C5)-alkenyl which is unsubstituted or substituted by a substituent selected from phenyl, cyano, hydroxycarbonyl, and (C1-C4)-alkoxycarbonyl;
k) (C2-C5)-alkynyl which is unsubstituted or substituted by a substituent selected from phenyl and (C1-C4)-alkoxy;
l) monocyclic or bicyclic heteroaryl having one or two identical or different ring heteroatoms selected from oxygen, sulfur, and nitrogen;
m) xe2x80x94S(O)m-phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl; or
n) xe2x80x94S(O)mxe2x80x94(C1-C4)-alkyl;
R(2) is hydrogen, (C1-C6)-alkyl, or (C3-C7)-cycloalkyl, but is not hydrogen if Z is oxygen;
the residues R(3) and R(4), which are independent of one another and can be identical or different, are phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl, hydrogen, or (C1-C4)-alkyl;
the residues R(5), which are independent of one another and can be identical or different, are hydrogen or (C1-C3)-alkyl;
m is 0, 1, or2;
n is 1, 2, 3, or 4;
in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof,
where compounds of formula I are excluded in which, simultaneously, X is oxygen, Z is NH, R(1) is halogen, (C1-C4)-alkyl, or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and R(2) is (C2-C6)-alkyl or (C5-C7)-cycloalkyl.
If groups, residues, substituents, or variables can occur several times in compounds of formula I, they can all independently of one another have the meanings indicated and can in each case be identical or different.
The term alkyl denotes straight-chain or branched saturated hydrocarbon residues. This also applies to residues derived therefrom such as, for example, alkoxy, alkoxycarbonyl, or the residue xe2x80x94S(O)m-alkyl. Examples of alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, or isohexyl. Examples of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, or tert-butoxy. The same applies to substituted alkyl residues, for example phenyl-alkyl- residues, or to divalent alkyl residues (alkanediyl residues), in which the substituents or the bonds via which the residues are bonded to the neighboring groups can be situated in any desired positions. Examples of alkyl residues of this type, which are bonded to two neighboring groups and which, inter alia, can represent the group Y, are xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2-CH2xe2x80x94.
Alkenyl and alkynyl denote straight-chain or branched, mono- or polyunsaturated hydrocarbon residues, in which the double bonds and/or triple bonds can be situated in any desired positions. Preferably, the residues alkenyl and alkynyl contain one double bond or one triple bond. Examples of alkenyl and alkynyl are vinyl, prop-2-enyl (allyl), prop-1-enyl, but-2-enyl, but-3-enyl, 3-methylbut-2-enyl, pent-2,4-dienyl, ethynyl, prop-2-ynyl (propargyl), prop-1-ynyl, but-2-ynyl, and but-3-ynyl. In substituted alkenyl residues and alkynyl residues, the substituents can be situated in any desired positions.
Examples of cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
Halogen is fluorine, chlorine, bromine, or iodine, preferably chlorine or fluorine.
In substituted phenyl residues, the substituents can be situated in any desired positions. In monosubstituted phenyl residues, the substituent can be situated in the 2-position, the 3-position, or the 4-position. In disubstituted phenyl residues, the substituents can be situated in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position, or 3,5-position. If a phenyl residue carries three substituents, these can be situated in the 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position, or 3,4,5-position. If a phenyl residue carries a further phenyl residue as a substituent, this second phenyl residue can also be unsubstituted or substituted by the substituents which are given for the first phenyl residue (apart from by a phenyl residue).
Heteroaryl is understood as meaning residues of monocyclic or bicyclic aromatic ring systems, which in the case of the monocyclic systems have a 5-membered ring or a 6-membered ring, and in the case of the bicyclic systems have two fused 5-membered rings, a 6-membered ring fused to a 5-membered ring, or two fused 6-membered rings. The heteroaryl residues can be conceived as being residues derived from cyclopentadienyl, phenyl, pentalenyl, indenyl, or naphthyl by replacement of one or two CH groups and/or CH2 groups by S, O, N, NH (or N carrying a substituent such as, for example, Nxe2x80x94CH3), where the aromatic ring system is retained or an aromatic ring system is formed. In addition to the one or two ring heteroatoms, they contain three to nine ring carbons. Examples of heteroaryl are, in particular, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, 1,3-oxazolyl, 1,2-oxazolyl, 1,3-thiazolyl, 1,2-thiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolyl, benzofuranyl, quinolyl, isoquinolyl, or benzopyranyl. A heteroaryl residue can be bonded via any suitable carbon. For example, a thienyl residue can be present as a 2-thienyl residue or 3-thienyl residue, a furyl residue as a 2-furyl residue or 3-furyl residue, and a pyridyl residue as a 2-pyridyl residue, 3-pyridyl residue, or 4-pyridyl residue. A residue which is derived from 1,3-thiazole or from imidazole can be bonded via the 2-position, the 4-position, or the 5-position. Suitable nitrogen heterocycles can also be present as N-oxides or as quaternary salts having an anion derived from a physiologically tolerable acid as a counterion. Pyridyl residues can be present, for example, as pyridine N-oxides.
If two ring oxygens are present in a saturated 4-membered to 7-membered heterocycle containing one or two oxygens as ring heteroatoms, these are not bonded directly to one another, but at least one ring carbon is situated between them. Examples of saturated 4-membered to 7-membered heterocycles which contain one or two oxygens as ring heteroatoms are oxetane, tetrahydrofuran, tetrahydropyran, oxepane, 1,3-dioxolane, or 1,4-dioxane. Preferred heterocycles are those which contain one ring oxygen. Particularly preferred heterocycles are tetrahydrofuran and tetrahydropyran. The saturated oxygen heterocycles can be bonded via any ring carbon, oxetane, for example, via the 2-position or the 3-position, tetrahydrofuran via the 2-position or the 3-position, tetrahydropyran via the 2-position, the 3-position, or the 4-position, 1,3-dioxolane via the 2-position or the 4-position. Tetrahydrofuran and tetrahydropyran are preferably bonded via the 2-position.
The present invention includes any stereoisomeric form of compounds of formula I. Asymmetric centers present in compounds of formula I can all independently of one another have the S configuration or the R configuration or the compounds can be present as an R/S mixture with respect to any of the asymmetric centers. The invention includes all possible enantiomers and diastereomers, as well as mixtures of at least two stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in any ratio. Enantiomers, for example, are thus a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates, and in the form of mixtures of the two enantiomers in any ratio. In the presence of cis/trans isomerism (or E/Z isomerism), both the cis form and the trans form and mixtures of these forms in any ratio are a subject of the invention. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture according to customary methods, for example by chromatography or crystallization, or by use of stereochemically uniform starting substances in the synthesis or by stereoselective reactions. If appropriate, a derivatization or salt formation can be carried out before separation of stereoisomers. The separation of a stereoisomer mixture can be carried out at the stage of compounds of formula I or at the stage of an intermediate in the course of the synthesis. The invention also includes all tautomeric forms of compounds of formula I.
Physiologically tolerable salts of compounds of formula I are, in particular, nontoxic salts or pharmaceutically utilizable salts. They can contain inorganic or organic salt components. Such salts can be prepared, for example, from compounds of formula I which contain at least one acidic group, and nontoxic inorganic or organic bases. Possible bases are, for example, suitable alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide or potassium hydroxide, or ammonia or organic amino compounds or quaternary ammonium hydroxides. Reactions of compounds of formula I with bases for the preparation of the salts are in general carried out in a solvent or diluent according to customary procedures. On account of the physiological and chemical stability, advantageous salts are, in the presence of acidic groups, in many cases sodium, potassium, magnesium, or calcium salts or ammonium salts which can carry at least one organic residue on the nitrogen. Salt formation on the nitrogen of the benzenesulfonamide group leads to compounds of formula II 
in which A(1), A(2), A(3), R(1), R(2), R(3), R(4), X, Y, and Z have the meanings indicated above, and the cation M, for example, is an alkali metal ion or an equivalent of an alkaline earth metal ion, for example the sodium, potassium, magnesium, or calcium ion, or the unsubstituted ammonium ion or an ammonium ion having at least one organic residue. An ammonium ion which is M can also be, for example, the cation which is obtained from an amino acid by protonation, in particular a basic amino acid such as, for example, lysine or arginine.
Compounds of formula I which contain at least one basic, that is protonatable, group can be present in the form of their acid addition salts with physiologically tolerable inorganic or organic acids and are used according to the invention, for example, as salts with hydrogen chloride, phosphoric acid, sulfuric acid, or organic carboxylic acids or sulfonic acids such as, for example, p-toluenesulfonic acid, acetic acid, tartaric acid, benzoic acid, fumaric acid, maleic acid, or citric acid. Acid addition salts can also be obtained from compounds of formula I by customary processes known to the person skilled in the art, for example by combination with an organic or inorganic acid in a solvent or diluent. If compounds of formula I simultaneously contain acidic and basic groups in the molecule, the present invention also includes, in addition to the salt forms described, inner salts or betaines (zwitterions). The present invention also includes all salts of compounds of formula I which, because of low physiological tolerability, are not directly suitable for use in pharmaceuticals, but are suitable, for example, as intermediates for chemical reactions or for the preparation of physiologically tolerable salts, for example by anion exchange or cation exchange.
The present invention furthermore includes all solvates of compounds of formula I, for example hydrates or adducts with alcohols, and also derivatives of compounds of formula I such as, for example, esters and amides of acid groups, and prodrugs and active metabolites of compounds of formula I.
In compounds of formula I, X is preferably oxygen or sulfur. A particularly preferred group of compounds is formed by those compounds in which X is sulfur and Z is NH. In compounds of formula I in which Z is oxygen, X is particularly preferably oxygen. A particularly preferred group of compounds of formula I is also formed by those compounds in which X is oxygen and, simultaneously, R(4) is hydrogen or (C1-C4)-alkyl, where in a very particularly preferred subgroup of these compounds R(2) is methyl.
Y is preferably the residue xe2x80x94(CR(5)2)nxe2x80x94 in which the residues R(5) are hydrogen or methyl, particularly preferably hydrogen. n is preferably 2 or 3, particularly preferably 2. An especially preferred group Y is the group xe2x80x94CH2xe2x80x94CH2xe2x80x94.
Z is preferably NH, that is preferred compounds of formula I are benzenesulfonamide derivatives of formula Ia 
in which A(1), A(2), A(3), R(1), R(2), R(3), R(4), X, and Y have the meanings indicated above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof. Particularly preferred compounds of formula la are those compounds in which X is oxygen or sulfur, that is compounds that are benzenesulfonylurea derivatives or benzenesulfonylthiourea derivatives.
The residues A(1), A(2), and A(3) can be situated in any desired positions in the phenyl ring to which they are bonded, as was generally explained above with respect to substituents in phenyl residues. If one of the residues A(1), A(2), or A(3) is hydrogen and the two others have a meaning other than hydrogen, the two residues different from hydrogen are preferably in the 2,4-position. The positions in the phenyl residue to which none of the residues A(1), A(2), and A(3) are bonded carry hydrogens. Preferably, one of the residues A(1), A(2), or A(3) is hydrogen and the two others are identical or different residues selected from hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, formyl, and trifluoromethyl, that is the phenyl residue carrying the residues A(1), A(2), and A(3) is preferably unsubstituted or substituted by one or two identical or different substituents. Particularly preferably, one of the residues A(1), A(2), or A(3) is hydrogen, one of the residues A(1), A(2), or A(3) is hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, formyl, or trifluoromethyl, and one of the residues A(1), A(2), or A(3) is halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, formyl, or trifluoromethyl, that is the phenyl residue carrying the residues A(1), A(2), and A(3) is particularly preferably a substituted phenyl residue which carries one or two identical or different substituents. If the residues A(1), A(2), and A(3) have a meaning other than hydrogen, they are preferably identical or different residues selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, and trifluoromethyl, in particular identical or different residues selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, and trifluoromethyl. Especially preferably, the residues A(1), A(2), and A(3) are identical or different residues selected from hydrogen, methyl, methoxy, ethoxy, fluorine, chlorine, and trifluoromethyl. In an especially preferred embodiment, the phenyl residue carrying the residues A(1), A(2), and A(3) is a substituted phenyl residue which carries one or two identical or different substituents selected from methyl, methoxy, ethoxy, fluorine, chlorine, and trifluoromethyl. It is moreover preferred if the phenyl residue carrying the residues A(1), A(2), and A(3) is a 2,4-dimethoxyphenyl residue.
A residue (C1-C4)-alkyl representing R(1) is preferably one of the residues methyl, ethyl, or isopropyl. A residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl representing R(1) is preferably one of the residues methoxy or ethoxy, in particular methoxy.
In the residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)xe2x80x94(C1-C4)-alkyl-D(1) representing R(1), the groups E(1), E(2), and E(3), which can be present therein, are preferably oxygen. D(1) is preferably hydrogen. If D(1) has a meaning other than hydrogen, D(2) is preferably hydrogen. Preferred meanings of the residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)xe2x80x94(C1-C4)-alkyl-D(1) are xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl and xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl, a particularly preferred meaning is xe2x80x94Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94(C1-C4)-alkyl. Especially preferred meanings of the residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)xe2x80x94(C1-C4)-alkyl-D(1) are 2-methoxyethoxy- and 2-(2-methoxyethoxy)ethoxy-, in particular 2-methoxyethoxy-.
A residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl representing R(1) which is substituted by a residue of an oxygen heterocycle, is preferably one of the residues tetrahydrofuran-2-ylmethoxy or tetrahydropyran-2-ylmethoxy. A residue xe2x80x94Oxe2x80x94(C2-C4)-alkenyl representing R(1) is preferably allyloxy. A residue xe2x80x94Oxe2x80x94(C1-C4)-alkyl-phenyl representing R(1) is preferably benzyloxy. A residue xe2x80x94O-phenyl representing R(1) is preferably unsubstituted or monosubstituted phenoxy, particularly preferably unsubstituted phenoxy or phenoxy substituted in the 4-position, in particular unsubstituted phenoxy, 4-methylphenoxy, 4-methoxyphenoxy, 4-fluorophenoxy, or 4-trifluoromethylphenoxy. Halogen representing R(1) is preferably bromine or iodine.
A phenyl residue representing R(1) is preferably unsubstituted or monosubstituted phenyl, particularly preferably unsubstituted phenyl or phenyl substituted in the 4-position, in particular unsubstituted phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, or 4-trifluoromethylphenyl, especially unsubstituted phenyl. A residue (C2-C5)-alkenyl representing R(1) is preferably allyl. A residue (C2-C5)-alkynyl representing R(1) is preferably ethynyl. A heteroaryl residue representing R(1) preferably contains one heteroatom and is preferably a monocyclic residue, particularly preferably a pyridyl residue, thienyl residue, or furyl residue, in particular one of the residues 2-pyridyl, 3-pyridyl, 2-thienyl, and 2-furyl, especially 2-furyl.
A residue xe2x80x94S(O)m-phenyl representing R(1) is preferably unsubstituted or monosubstituted xe2x80x94S(O)m-phenyl, particularly preferably unsubstituted xe2x80x94S(O)m-phenyl, especially the unsubstituted residue xe2x80x94S-phenyl. A residue xe2x80x94S(O)mxe2x80x94(C1-C4)-alkyl which is
R(1) is preferably xe2x80x94S(O)m-methyl, in particular xe2x80x94S-methyl.
m is preferably 0 or 2, particularly preferably 0.
R(1) is preferably
a) methyl, ethyl, or isopropyl;
b) methoxy or ethoxy;
c) 2-methoxyethoxy;
d) tetrahydrofuran-2-ylmethoxy or tetrahydropyran-2-ylmethoxy;
e) allyloxy;
f) benzyloxy;
g) phenoxy, 4-methylphenoxy, 4-methoxyphenoxy, 4-fluorophenoxy, or 4-trifluoromethylphenoxy;
h) bromine or iodine;
i) phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, or 4-trifluoromethylphenyl;
j) allyl;
k) ethynyl;
l) pyridyl, furyl, or thienyl;
m) xe2x80x94S-phenyl; or
n) xe2x80x94S-methyl.
Particularly preferably, R(1) is one of the residues mentioned in the general or in a preferred definition of R(1) which are bonded to the benzene ring carrying the group R(1) via an oxygen, or an optionally substituted phenyl residue or heteroaryl residue. Very particularly preferably, R(1) is one of the residues methoxy, 2-methoxyethoxy-, tetrahydrofuran-2-ylmethoxy-, tetrahydropyran-2-ylmethoxy-, allyloxy, benzyloxy, and phenoxy, especially preferably one of the residues methoxy and 2-methoxyethoxy.
If Z is NH, R(2) is preferably hydrogen, (C1-C4)-alkyl, or (C3-C6)-cycloalkyl, particularly preferably hydrogen, methyl, ethyl, isopropyl, or cyclohexyl. A group of very particularly preferred compounds of formula I in which Z is NH, is formed by compounds in which R(2) is hydrogen or methyl, another group is formed by compounds in which R(2) is methyl, ethyl, isopropyl, or cyclohexyl. If Z is oxygen, R(2) is preferably (C1-C4)-alkyl. An especially preferred meaning of R(2) is methyl.
R(3) is preferably hydrogen, methyl, or unsubstituted phenyl, particularly preferably hydrogen. R(4) is preferably hydrogen.
Preferred compounds of formula I are those in which at least one of the residues contained therein have preferred meanings, where all combinations of preferred substituent definitions are a subject of the present invention. Also with respect to all preferred compounds of formula I, the present invention includes any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof. Also from the preferred compounds which are a subject of the present invention per se, those compounds are excluded which are excluded above from the general definition of compounds of formula I by the disclaimer.
Thus, for example, a group of preferred compounds is formed by those compounds of formula I in which Z is NH, X is sulfur, and R(2) is methyl, and the other residues have the general or preferred meanings indicated above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
A group of preferred compounds is also formed by those compounds of formula I, in which:
Y is xe2x80x94CH2xe2x80x94CH2xe2x80x94;
one of the residues A(1), A(2), and A(3) is hydrogen and the other two are identical or different residues selected from hydrogen, methyl, methoxy, ethoxy, fluorine, chlorine, and trifluoromethyl;
R(2) is methyl, ethyl, isopropyl, or cyclohexyl;
R(3) and R(4) are hydrogen; and
R(1), X, and Z have the general or preferred meanings indicated above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof. Particularly preferred subgroups of these compounds are formed by compounds of formula I in which Z is NH and/or X is sulfur. A very particularly preferred subgroup is formed by compounds of formula I in which R(2) is methyl.
A group of particularly preferred compounds is formed, for example, by compounds of formula Ib 
in which:
X is oxygen or sulfur;
R(1) is methoxy, 2-methoxyethoxy-, tetrahydrofuran-2-ylmethoxy-, tetrahydropyran-2-ylmethoxy-, allyloxy, benzyloxy, or phenoxy;
R(2) is methyl, ethyl, isopropyl, or cyclohexyl; in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
A preferred meaning of R(2) in compounds of formula Ib is methyl. Preferably, the residue X in compounds of formula lb is sulfur. A group of very particularly preferred compounds is thus formed by compounds of formula Ib in which:
X is sulfur;
R(1) is methoxy, 2-methoxyethoxy-, tetrahydrofuran-2-ylmethoxy-, tetrahydropyran-2-ylmethoxy-, allyloxy, benzyloxy, or phenoxy;
R(2) is methyl, ethyl, isopropyl, or cyclohexyl;
in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof, where also in these compounds, R(2) is preferably methyl.
The present invention also relates to processes for the preparation of compounds of formula I which are explained below and by which compounds according to the invention are obtainable.
Compounds of formula I in which X is sulfur and Z is NH, that is benzenesulfonylthioureas of formula Ic 
in which A(1), A(2), A(3), R(1), R(2), R(3), R(4), and Y have the abovementioned meanings, can be prepared, for example, by reacting benzenesulfonamides of formula III 
in which A(1), A(2), A(3), R(1), R(3), R(4), and Y have the abovementioned meanings, in an inert solvent or diluent with a base and with an R(2)-substituted isothiocyanate of formula IV
R(2)xe2x80x94Nxe2x95x90Cxe2x95x90Sxe2x80x83xe2x80x83IV
in which R(2) has the meanings indicated above. Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, or quaternary ammonium hydroxides. The reaction of the compound of formula IlIl with the base can first be carried out in a separate step and the initially resulting salt of formula V 
in which A(1), A(2), A(3), R(1), R(3), R(4), and Y have the abovementioned meanings, and M1 is an alkali metal ion, for example sodium or potassium, or an equivalent of an alkaline earth metal ion, for example magnesium or calcium, or an ammonium ion which is inert under the reaction conditions, for example a quaternary ammonium ion, can, if desired, also be intermediately isolated. The salt of formula V, however, can particularly advantageously also be produced in situ from the compound of formula III and reacted directly with the isothiocyanate of formula IV. Suitable inert solvents for the reaction are, for example, ethers such as tetrahydrofuran (THF), dioxane, ethylene glycol dimethyl ether (DME), or diglyme, ketones such as acetone or butanone, nitrites such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), hexamethylphosphortriamide (HMPT), sulfoxides such as dimethyl sulfoxide (DMSO), or hydrocarbons such as benzene, toluene, or xylenes. Mixtures of these solvents with one another are furthermore suitable. The reaction of compounds of formula III and/or V with the compound of formula IV is usually carried out at temperatures from room temperature to 150xc2x0 C.
Compounds of formula I in which X is oxygen and Z is NH, that is benzenesulfonylureas of formula Id 
in which A(1), A(2), A(3), R(1), R(2), R(3), R(4), and Y have the abovementioned meanings, can be prepared, for example, by reacting, analogously to the synthesis of thiourea derivatives of formula Ic described above, benzenesulfonamides of formula III and/or their salts of formula V in an inert solvent or diluent with a base and with an R(2)-substituted isocyanate of formula VI
xe2x80x83R(2)xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83VI
in which R(2) has the meanings indicated above. The above explanations for the reaction with isothiocyanates correspondingly apply to the reaction with isocyanates.
Benzenesulfonylureas of formula Id can also be prepared from benzenesulfonamides of formula IlIl and/or their salts of formula V by reaction with R(2)-substituted 2,2,2-trichloroacetamides of formula VII
Cl3Cxe2x80x94COxe2x80x94NHxe2x80x94R(2)xe2x80x83xe2x80x83VII
in which R(2) has the meanings indicated above, in the presence of a base in an inert high-boiling solvent such as, for example, DMSO.
Benzenesulfonylureas of formula Id can also be prepared from the corresponding benzenesulfonylthioureas of formula Ic by a conversion reaction (desulfurization). The replacement of sulfur in the thiourea group of compounds of formula Ic by an oxygen can be carried out, for example, with the aid of oxides or salts of heavy metals or by use of oxidants such as hydrogen peroxide, sodium peroxide, or nitrous acid.
Benzenesulfonylureas and -thioureas of formulae Id and Ic can also be prepared by reaction of amines of formula R(2)xe2x80x94NH2 with benzenesulfonyl isocyanates and isothiocyanates of formula VIII 
in which A(1), A(2), A(3), R(1), R(3), R(4), and Y have the abovementioned meanings, and X is oxygen or sulfur. Sulfonyl isocyanates of formula VIII (X=oxygen) can be obtained from benzenesulfonamides of formula III according to customary methods, for example using phosgene. Sulfonyl isothiocyanates of formula VIII (X=sulfur) can be prepared by reaction of the sulfonamide of formula III with alkali metal hydroxides and carbon disulfide in an organic solvent such as DMF, DMSO, or NMP. The di-alkali metal salt of the sulfonyidithiocarbamic acid obtained in this case can be reacted in an inert solvent with a slight excess of phosgene or of a phosgene substitute such as triphosgene or with a chloroformic acid ester (2 equivalents) or with thionyl chloride. The solution of the sulfonyl iso(thio)cyanate of formula VIII obtained can be reacted directly with the appropriate substituted amine of formula R(2)xe2x80x94NH2 or, if compounds of formula I are to be prepared in which R(2) is hydrogen, with ammonia.
Correspondingly, starting from benzenesulfonyl iso(thio)cyanates of formula VIII, by means of addition of alcohols of formula R(2)xe2x80x94OH compounds of formula I can be prepared in which Z is oxygen, that is benzenesulfonylurethane derivatives of formula Ie 
in which A(1), A(2), A(3), R(1), R(2), R(3), R(4), and Y have the abovementioned meanings, but as mentioned R(2) is not hydrogen, and X is oxygen or sulfur. Compounds of formula Ie can also be prepared, for example by reacting, analogously to the syntheses described above, benzenesulfonamides of formula III and/or their salts of formula V in an inert solvent, for example a high-boiling ether, with reactive carbonic acid derivatives, for example with chloroformic acid esters of formula Clxe2x80x94COxe2x80x94OR(2) or pyrocarbonic acid diesters of formula (R(2)Oxe2x80x94C(xe2x95x90O))2O. Starting from compounds of formula Ie in which X is oxygen, compounds of formula Id are obtainable by action of the appropriate amine of formula R(2)xe2x80x94NH2 in an inert high-boiling solvent, for example toluene, at temperatures up to the boiling point of the respective solvent.
Compounds of formula I in which X is the cyanoimino group xe2x95x90Nxe2x80x94CN are obtainable, for example, by reacting diphenyl N-cyanoiminocarbonates of formula NCxe2x80x94Nxe2x95x90C(Oxe2x80x94C6H5)2 with a benzenesulfonamide of formula III and/or its salt of formula V in the presence of a base, and then treating the N-cyanoxe2x80x94Oxe2x80x94 phenylbenzenesulfonylisourea obtained as an intermediate with an amine of formula R(2)xe2x80x94NH2.
Benzenesulfonamides of formula III as starting compounds for the abovementioned processes for the synthesis of benzenesulfonyl(thio)ureas of formula I can be prepared by or analogously to known methods such as are described in the literature, for example in the standard works such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, and Organic Reactions, John Wiley and Sons, Inc., New York, and also in the patent documents indicated above, if appropriate with suitable adaptation of the reaction conditions which is familiar to the person skilled in the art. Use can also be made of synthetic variants which are known per se, but not mentioned here in greater detail. In the syntheses, it may also be appropriate to temporarily block functional groups which would react in an undesired manner or give rise to side reactions, by protective groups or to employ them in the form of precursor groups which are converted into the desired groups only later. Strategies of this type are known to the person skilled in the art. Starting substances, if desired, can also be formed in situ in such a way that they are not isolated from the reaction mixture but immediately reacted further.
Thus, for example, p-substituted benzene derivatives of formula IX 
in which Y has the abovementioned meanings and R(0), for example, is (C1-C4)-alkyl, (C1-C4)-alkoxy, bromine, or nitro, can be reacted with trifluoroacetic anhydride in the presence of pyridine in an inert solvent such as THF to give compounds of formula X 
in which Y and R(0) have the meanings indicated above.
Starting from compounds of formula X in which R(0) is nitro, it is possible by means of a reduction of the nitro group using a reductant such as, for example, SnCl2xc3x972 H2O in an inert solvent such as ethyl acetate, diazotization of the resulting amino group, and subsequent reaction of the intermediate diazo compound by processes known per se, such as are described, for example, in Larock, Comprehensive Organic Transformations, VCH, (1989), for example by reaction with potassium iodide for the preparation of the iodo compounds, to obtain the corresponding p-halo-substituted compounds of formula Xl 
in which Y has the meanings indicated above and Hal is halogen.
Compounds of formula XI and compounds of formula X in which R(0) is (C1-C4)-alkyl, (C1-C4)-alkoxy, or bromine, which are summarily designated as compounds of formula XII 
in which Y has the meanings indicated above, and R(1a) is (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen, can be converted in a manner known per se into the benzenesulfonamides of formula XIII 
in which Y and R(1a) have the meanings mentioned. Sulfonamides of formula XIII can be prepared from compounds of formula XII in at least one step. In particular, processes are preferred in which acylamines of formula XII are first converted into 2,5-substituted benzenesulfonic acids or their derivatives such as, for example, sulfonyl halides, by electrophilic reagents in the presence or absence of inert solvents at temperatures of xe2x88x9220xc2x0 C. to 120xc2x0 C., preferably of 0xc2x0 C. to 100xc2x0 C. For this, it is possible to carry out, for example, sulfonations with sulfuric acids or oleum, halosulfonations with halosulfonic acids such as chlorosulfonic acid, reactions with sulfuryl halides in the presence of anhydrous metal halides, or reactions with thionyl halides in the presence of anhydrous metal halides with subsequent oxidations carried out in a known manner to give sulfonyl chlorides. If sulfonic acids are the primary reaction products, these can either be converted into sulfonyl acid halides directly in a manner known per se by means of acid halides such as, for example, phosphorus trihalides, phosphorus pentahalides, thionyl halides, or oxalyl halides, or after treatment with amines such as, for example, triethylamine or pyridine, or alkali metal or alkaline earth metal hydroxides or reagents which form these basic compounds in situ. Sulfonic acid derivatives are converted into sulfonamides of formula XIII in a manner known from the literature. Preferably, sulfonyl acid chlorides are reacted with aqueous ammonia in an inert solvent such as, for example, acetone at temperatures of 0xc2x0 C. to 100xc2x0 C.
For the preparation of compounds of formula I in which R(1) is (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen, compounds of formula XIII can be converted by treatment with an acid such as, for example, hydrochloric acid or sulfuric acid, if appropriate with addition of a polar organic solvent such as methanol or ethanol, at temperatures of 0xc2x0 C. up to the boiling point of the solvent, into compounds of formula XIV 
in which R(1a) is (C1-C4)-alkyl, (C1-C4)-alkoxy, or halogen, and Y has the meanings indicated above. For the preparation of compounds of formula I in which R(1) denotes the other abovementioned residues, the sulfonamide group in suitable compounds of formula XIII can first be temporarily protected by conversion into the N-(N,N-dimethylaminomethylene)sulfonamide group. For example, starting from compounds of formula XIII, dimethylaminomethylene compounds of formula XV 
in which Y has the meanings mentioned, and R(1b) is (C1-C4)-alkoxy, bromine, or iodine, can be prepared by reacting compounds of formula XIII, for example, with N,N-dimethylformamide dimethyl acetal or reacting with N,N-dimethylformamide in the presence of dehydrating agents such as thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride.
Compounds of formula XV in which R(1b) is (C1-C4)-alkoxy can then be converted by ether cleavage into phenols of formula XVI 
in which Y is as defined above. This ether cleavage is carried out, for example, by treatment of methoxy compounds of formula XV with acids or with Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, or aluminum trichloride, or their etherates, preferably with boron tribromide in an inert solvent such as, for example, methylene chloride.
Phenols of formula XVI obtained can be converted into compounds of formula XVII 
in which Y has the abovementioned meanings and R(1c) is one of the residues xe2x80x94Oxe2x80x94(C1-C4)-alkyl-E(1)xe2x80x94(C1-C4)-alkyl-D(1), xe2x80x94Oxe2x80x94(C1-C4)-alkyl which is substituted by an oxygen heterocycle, xe2x80x94Oxe2x80x94(C2-C4)-alkenyl, xe2x80x94Oxe2x80x94(C1-C4)-alkyl-phenyl, or xe2x80x94O-phenyl. This conversion is carried out by means of an O-alkylation of phenols of formula XVI using appropriately substituted halogen compounds, for example iodides or bromides, or appropriately substituted sulfonic acid esters such as mesylates, tosylates, or trifluoromethylsulfonates. Thus, for example, with 2-bromoethyl methyl ether or benzyl bromide, compounds of formula I are obtained in which R(1) is 2-methoxyethoxy- or benzyloxy. The O-alkylation is in general carried out in the presence of a base in an inert solvent at temperatures of 0xc2x0 C. up to the boiling point of the solvent by processes known per se. The preparation of compounds of formula XVII in which R(1c) is xe2x80x94O-phenyl is carried out by means of an O-arylation of phenols of formula XVI using phenylboronic acids, for example phenylboronic acid or substituted phenylboronic acids such as 4-methoxyphenylboronic acid, in the presence of copper catalysts, for example copper(lI) acetate, for example analogously to the reactions described in Tetrahedron Lett. 39 (1998) 2937.
Starting from compounds of formula XV in which R(1b) is bromine or iodine, compounds of formula XVIII 
can be obtained in which Y has the meanings indicated, and R(1d) is one of the residues (C1-C4)-alkyl, phenyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, heteroaryl, xe2x80x94S(O)m-phenyl, or xe2x80x94S(O)mxe2x80x94(C1-C4)-alkyl. This conversion into compounds of formula XVIII is carried out by means of palladium-catalyzed Suzuki coupling with arylboronic acids, for example phenylboronic acid, 4-methoxyphenylboronic acid, or 4-methylthiophenylboronic acid, or heteroarylboronic acids, for example thienylboronic acid, or by Stille coupling with trialkylstannanes, for example tributylstannylfuran, trimethylstannylpyridine, or ethynyltributylstannane. The Suzuki coupling is carried out in the presence of palladium(II) acetate and triphenylphosphine or tetrakis(triphenylphosphine)palladium and a base such as, for example, cesium carbonate or potassium carbonate; corresponding reactions are described in the literature. The Stille coupling is carried out analogously to literature procedures using bis(triphenylphosphine)palladium(II) chloride as a catalyst. The preparation of suitable stannanes is described, for example, in Tetrahedron 49 (1993) 3325. The preparation of compounds of formula XVIII in which R(1d) is alkyl is carried out by Pd(0)-catalyzed Nikishi-Kumada coupling of compounds of formula XV in which R(1b) is iodine with an appropriate organozinc derivative in the presence of 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, palladium(II) acetate, and copper(I) iodide as catalysts in an inert solvent; corresponding couplings are described, for example, in Synlett (1996) 473.
Compounds of formula XVIII in which R(1d) is xe2x80x94S-phenyl or xe2x80x94S-(C1-C4)-alkyl can be prepared analogously to literature procedures by means of a copper(I) iodidecatalyzed nucleophilic substitution reaction from compounds of formula XV in which R(1b) is iodine, using the sodium salt of the corresponding mercaptan. The thioether group thus introduced, and also a thioether group in another position of the molecule of formula I, can be oxidized to the sulfoxide group or to the sulfone group by standard processes, for example using a peracid such as m-chloroperbenzoic acid.
The subsequent removal of the dimethylaminomethylene group and/or the trifluoroacetyl group functioning as a sulfonamide protective group or amino protective group, respectively, from compounds of formulae XVII and XVIII then leads to the corresponding compounds having an H2Nxe2x80x94Y group and H2Nxe2x80x94SO2 group, which are represented together with compounds of formula XIV by formula XIX 
in which Y and R(1) have the meanings indicated above for formula I. This removal of the protective groups can be carried out either under basic or under acidic conditions. Preferably, it is carried out by treatment of compounds of formulae XVII and XVIII in a suitable solvent, for example an alcohol, with acids such as, for example, hydrochloric acid.
Benzenesulfonamides of formula XIX are then reacted with cinnamic acid derivatives to give cinnamoylaminoalkyl-substituted benzenesulfonamides of formula III. In general, this acylation is carried out by first converting the appropriate cinnamic acid into a reactive derivative, for example by reaction of the cinnamic acid with carbonylbisimidazole in an inert solvent such as, for example, THF, dioxane, or DMF, and subsequent reaction with the amine of formula XIX, if appropriate in the presence of a base such as triethylamine or pyridine. Reactive cinnamic acid derivatives which can be used, for example, are also cinnamic acid halides or cinnamic anhydrides. The reactions are in this case preferably carried out at temperatures from 0xc2x0 C. up to the boiling point of the solvent chosen, particularly preferably at room temperature. The acylation of amines of formula XIX with cinnamic acids can also be carried out, for example, in the presence of condensing agents such as, for example, N,Nxe2x80x2-dicyclohexylcarbodiimide, O-((cyano-(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU), or 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP).
The steps for the preparation of compounds of formula I described can also be carried out in other sequences. Depending on the substituents to be introduced in the individual steps, one or the other variants can be more advantageous. Thus, for example, the preparation of compounds of formula III in which R(1) is one of the residues (C1-C4)-alkyl, phenyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, heteroaryl, xe2x80x94S(O)m-phenyl, or xe2x80x94S(O)mxe2x80x94(C1-C4)-alkyl, can also be carried out in such a way that a compound of formula XIV in which R(1a) is iodine or bromine is first converted, by means of the coupling with a cinnamic acid derivative described above and temporary protection of the sulfonamide group, into a compound of formula XX 
in which A(1), A(2), A(3), R(3), R(4), and Y are defined as for formula I and Hal1 is iodine or bromine. Starting from the compound of formula XX, it is then possible by means of the Suzuki, Stille, or Nikishi-Kumada couplings described above with the appropriate coupling components mentioned above to obtain compounds of formula XXI 
in which A(1), A(2), A(3), R(ld), R(3), R(4), and Y have the meanings indicated above. Compounds of formula XXI can then be converted into compounds of formula III by removal of the sulfonamide protective group according to the process described above.
Compounds of formula I inhibit ATP-sensitive potassium channels and affect the action potential of cells, in particular of cardiac muscle cells. In particular, they have a normalizing action on a disturbed action potential, as is present, for example, in ischemias, and are suitable, for example, for the treatment and prophylaxis of disorders of the cardiovascular system, in particular of arrhythmias and their sequelae, for example of ventricular fibrillation. The activity of compounds of formula I can be demonstrated, for example, in the model described below in which the action potential duration is determined on the papillary muscle of the guinea pig.
In addition to their action on ATP-sensitive potassium channels in the heart muscle cell, compounds of formula I also have an action on the peripheral and/or the central autonomic nervous system. In particular, they affect ATP-sensitive potassium channels of the vagal nervous system and have a stimulating action on the vagal nervous system, in particular a stimulating action on the vagal nervous system of the heart by inhibition of ATP-sensitive potassium channels in the cardiac nerve.
In the ideal case, an optimum cooperation, adapted to the particular situation, exists between the vagal (or parasympathetic) nervous system (=depressing nervous system) and the sympathetic nervous system (=stimulating nervous system). In the case of disease, however, this cooperation can be disturbed and a dysfunction of the autonomic nervous system can be present, that is an imbalance can exist between the activity of the vagal nervous system and the activity of the sympathetic nervous system. Sympathovagal imbalance is understood in general as meaning an overactivity or hyperfunction of the sympathetic (=stimulating) nervous system and/or an impaired function or hypofunction of the vagal (=depressing) nervous system, where the two parts of the nervous system can mutually influence each other. In particular, it is known that a hypofunction of the vagal system can result in a hyperfunction of the sympathetic system. For the avoidance of damage to cells or organs of the body by overshooting biological or biochemical processes which are stimulated by too high an activity of the sympathetic nervous system, it is therefore attempted in such cases to balance out a sympathovagal imbalance, for example to restore the normal vagal activity by treating a vagal dysfunction or hypofunction.
Examples of diseases in which elimination of a harmful sympathovagal imbalance by treatment of a vagal dysfunction is possible are organic heart diseases, for example coronary heart disease, cardiac insufficiency, and cardiomyopathies. Damages to health which result from an imbalance of the autonomic nervous system when the dysfunction relates to the heart are, for example, weakening of the myocardial contractile force and fatal cardiac arrhythmias. The significance of the autonomic nervous system for sudden cardiac death in heart disease was described, for example, by P. J. Schwartz (xe2x80x9cThe ATRAMI prospective study: implications for risk stratification after myocardial infarction,xe2x80x9d Cardiac Electrophysiology Review 2 (1998) 38-40) or T. Kinugawa et al. (xe2x80x9cAltered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure,xe2x80x9d Am. J. Physiol. 37 (1995) R310-R316). Experimental investigations with electrical stimulation of the cardiac vagus nerve or stimulating analogs of the vagal transmitter acetylcholine, for example carbachol, confirm the protective action of a vagal activation against fatal cardiac arrhythmias (see, for example, E. Vanoli et al., xe2x80x9cVagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction,xe2x80x9d Circ. Res. 68(5) (1991) 1471-1481).
A sympathovagal imbalance, however, can also occur, for example, as a result of a metabolic disorder, for example diabetes mellitus (see, for example, A. J. Burger et al., xe2x80x9cShort- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus,xe2x80x9d Am. J. Cardiol. 80 (1997) 1198-1202). A hypofunction of the vagal system can also temporarily occur, for example in the case of oxygen deficiency, for example oxygen deficiency of the heart, which leads to an undersecretion of vagal neurotransmitters, for example of acetylcholine.
On account of the surprising ability of compounds of formula I to abolish a hypofunction of the vagal system or to restore the normal vagal activity, these compounds offer an efficient possibility of decreasing, eliminating, or preventing dysfunctions of the autonomic nervous system, in particular in the heart, and its consequences such as, for example, the disease conditions mentioned. The efficacy of compounds of formula I in the abolition of dysfunctions of the autonomic nervous system, in particular of a vagal dysfunction of the heart, can be demonstrated, for example, in the model of chloroform-induced ventricular fibrillation in the mouse described below.
The above and the following statements regarding the biological action on ATP-sensitive potassium channels in the heart and on the autonomic nervous system and the uses of compounds of formula I do not only apply to the compounds defined above which are per se a subject of the present invention, but also to compounds of formula I in which, simultaneously, X is oxygen, Z is NH, R(1) is halogen, (C1-C4)-alkyl, or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and R(2) is (C2-C6)-alkyl or (C5-C7)-cycloalkyl, or a physiologically tolerable salt or prodrug thereof, that is also to compounds which are excluded by the disclaimer in the above definition of the compounds but which likewise surprisingly have an action on the autonomic nervous system, in particular on the heart, and can abolish vagal dysfunctions. If not stated otherwise, in the above and the following statements regarding their biological action and use, compounds of formula I are expressly to be understood as including also the compounds excluded above by the disclaimer. The above explanations with respect to the compounds per se, for example with respect to preferred meanings of residues, correspondingly apply to all compounds of formula I as understood here. As particularly preferred groups of compounds with respect to the biological action and the uses, moreover those compounds of formula I, including compounds in which, at the same time, X is oxygen, Z is NH, R(1) is halogen, (C1-C4)-alkyl, or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and R(2) is (C2-C6)-alkyl or (C5-C7)-cycloalkyl, or a physiologically tolerable salt thereof, may be mentioned here in which R(2) is (C1-C3)-alkyl, in particular methyl, and/or X is sulfur.
Compounds of formula I, or a physiologically tolerable salt thereof, can be used as pharmaceuticals on their own, in mixtures with one another, or in the form of pharmaceutical preparations in animals, preferably in mammals, and in particular in humans. Mammals in which compounds of formula I can be used or tested are, for example, monkeys, dogs, mice, rats, rabbits, guinea pigs, cats, and larger farm animals such as, for example, cattle and pigs. The invention therefore also relates to compounds of formula I where the compounds are excluded in which, simultaneously, X is oxygen, Z is NH, R(1) is halogen, (C1-C4)-alkyl, or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and R(2) is (C2-C6)-alkyl or (C5-C7)-cycloalkyl, or a physiologically tolerable salt or a prodrug thereof for use as pharmaceuticals. The invention also relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an efficacious dose of at least one compound of formula I where the compounds are excluded in which, simultaneously, X is oxygen, Z is NH, R(1) is halogen, (C1-C4)-alkyl, or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and R(2) is (C2-C6)-alkyl or (C5-C7)-cycloalkylxe2x80x94and/or a physiologically tolerable salt and/or a prodrug thereof as an active constituent and at least one pharmaceutically tolerable carrier, that is at least one pharmaceutically innocuous vehicle and/or additive.
The pharmaceutical preparations can be intended for enteral or parenteral use and normally contain about 0.5 to about 90 percent by weight of the compound of formula I and/or a physiologically tolerable salt thereof. The amount of active compound of formula I and/or a physiologically tolerable salt thereof in the pharmaceutical preparations is in general about 0.2 to about 1000 mg, preferably about 1 to about 500 mg. The pharmaceutical preparations can be produced in a manner known per se. For this, compounds of formula I and/or a physiologically tolerable salt thereof are mixed together with at least one solid or liquid vehicle and/or excipient and, if desired, in combination with at least one other pharmaceutical, for example cardiovascular-active pharmaceuticals such as, for example, calcium antagonists, ACE inhibitors, or xcex2-blockers, and brought into a suitable dose form and administration form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
Suitable vehicles are organic and inorganic substances which are suitable, for example, for enteral (for example oral or rectal) administration or for parenteral administration (for example intravenous, intramuscular, or subcutaneous injection or infusion) or for topical or percutaneous application, and do not react with compounds of formula I in an undesired manner. Examples which may be mentioned are water, vegetable oils, waxes, alcohols such as ethanol, propanediol, or benzyl alcohols, glycerol, polyols, polyethylene glycols, polypropylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, stearic acid and its salts such as magnesium stearate, talc, lanolin, petroleum jelly, or mixtures of vehicles, for example mixtures of water with at least one organic solvent, such as mixtures of water with alcohols. For oral and rectal administration, in particular pharmaceutical forms such as tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, preferably oily, alcoholic, or aqueous solutions, syrups, juices, or drops, furthermore suspensions or emulsions, are used. For topical administration, in particular ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions, or powders are used. Solvents for solutions that can be used are, for example, water or alcohols such as ethanol, isopropanol, or 1,2-propanediol, or their mixtures with one another or with water. Further possible pharmaceutical forms are, for example, also implants. Compounds of formula I or a physiologically tolerable salt thereof can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. Liposomal preparations are also possible, in particular for topical application. Examples of excipients (or additives) which can be present in the pharmaceutical preparations and which may be mentioned are lubricants, preservatives, thickeners, stabilizing agents, disintegrants, wetting agents, agents for achieving a depot effect, emulsifiers, salts (for example for affecting the osmotic pressure), buffer substances, colorants, flavorings, and aromatizers. The pharmaceutical preparations, if desired, can also contain at least one further active compound and/or, for example, at least one vitamin.
On account of their ability to inhibit ATP-sensitive potassium channels, in particular in the heart, and/or to decrease or to eliminate an inadequate function of the vagal nervous system and thereby a vagal dysfunction or a dysfunction of the autonomic nervous system, in particular in the heart, compounds of formula I or a physiologically tolerable salt or prodrug thereof are valuable agents for therapy and prophylaxis which are suitable not only as antiarrhythmics and for the control and prevention of the sequelae of arrhythmias, but also for treatment and prophylaxis in other heart diseases or disorders of the cardiovascular system. Examples of diseases of this type which may be mentioned are cardiac insufficiency, cardiomyopathies, cardiac hypertrophy, coronary heart disease, angina pectoris, ischemias, vagal dysfunction of the heart, or, for example, vagal dysfunction of the heart in diabetes mellitus. Compounds of formula I can be generally employed in the therapy or prophylaxis of diseases which are associated with a dysfunction of the autonomic nervous system or a hypofunction or dysfunction of the vagal nervous system, in particular in the heart, or are caused by a dysfunction of this type or for whose therapy or prophylaxis an increase or normalization of the activity of the vagal nervous system is desired. Compounds of formula I can also be employed in dysfunctions of the autonomic nervous system, in particular a vagal dysfunction in the heart, which occur as a result of a metabolic disorder such as, for example, diabetes mellitus.
Above all, compounds of formula I are used as antiarrhythmics for the treatment of cardiac arrhythmias of very different origins and especially for the prevention of sudden cardiac death due to arrhythmia. Examples of arrhythmic disorders of the heart are supraventricular arrhythmias such as, for example, atrial tachycardia, atrial flutter, or paroxysmal supraventricular arrhythmias, or ventricular arrhythmias such as ventricular extrasystoles, but in particular life-threatening ventricular tachycardia or the particularly dangerous ventricular fibrillation. They are particularly suitable for those cases where arrhythmias are a result of a constriction of a coronary vessel such as occur, for example, in angina pectoris or during acute cardiac infarct or as a chronic result of a cardiac infarct. They are therefore particularly suitable in postinfarct patients for the prevention of sudden cardiac death. Further syndromes in which arrhythmias of this type and/or sudden cardiac death due to arrhythmia play a role are, for example, cardiac insufficiency or cardiac hypertrophy as a result of chronically raised blood pressure.
Moreover, compounds of formula I are able to positively affect decreased contractility of the heart and a weakened myocardial contractile force. This can be a disease-related decline in cardiac contractility, such as, for example, in cardiac insufficiency, but also acute cases such as heart failure as an effect of shock. Generally, compounds of formula I or a physiologically tolerable salt thereof are suitable for improving cardiac function. Especially in a heart transplantation, under the influence of compounds of formula I the heart can also resume its capability faster and more reliably after the operation has taken place. The same applies to operations on the heart which necessitate temporarily stopping cardiac activity by means of cardioplegic solutions.
By virtue of the fact that compounds of formula I, in addition to their direct cardiac action, that is the effect on the action potential of the cardiac muscle cells, also have an indirect action on the nervous system of the heart or the parts of the nervous system acting on the heart, they can decrease or prevent the undesired sequelae on the heart starting from the nervous system or mediated by the nervous system in the respective disease state present. Further damage to health such as a weakening of the myocardial contractile force or in some cases fatal cardiac arrhythmias such as ventricular fibrillation can thereby be reduced or avoided. Through the elimination or reduction of the dysfunction of the autonomic nervous system, compounds of formula I have the effect that the weakened myocardial contractile force is normalized again and the cardiac arrhythmias which can lead to sudden cardiac death can no longer result. By selection of compounds of formula I having a suitable profile of action with respect to direct cardiac action (=direct effect on the action potential of the cardiac muscle cells and on account of this direct effect on the contractile force and direct antiarrhythmic action) on the one hand and the action on the cardiac nerves on the other hand, it is possible in a particularly efficient manner with the aid of compounds of formula I to favorably influence heart diseases. Depending on the syndrome present, it can also be advantageous in this case to employ compounds of formula I which only have a relatively low direct cardiac effect and owing to this, for example, only have a relatively low direct effect on the contractile force of the heart or the formation of arrhythmias, but can improve or normalize the myocardial contractile force or the heart rhythm via the effect of the autonomic nervous system.
The present invention therefore also relates to the use of compounds of formula I xe2x80x94including compounds in which, at the same time, X is oxygen, Z is NH, R(1) is halogen, (C1-C4)-alkyl, or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and R(2) is (C2-C6)-alkyl or (C5-C7)-cycloalkylxe2x80x94and/or a physiologically tolerable salt and/or prodrug thereof, for the therapy or prophylaxis of the syndromes mentioned, and the use for the production of pharmaceuticals for the therapy or prophylaxis of the syndromes mentioned. Of compounds of formula I in which, simultaneously, X is oxygen, Z is NH, R(1) is halogen, (C1-C4)-alkyl, or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and R(2) is (C2-C6)-alkyl or (C5-C7)-cycloalkyl, preferred compounds for the therapy or prophylaxis of the syndromes mentioned and for the production of pharmaceuticals for the therapy or prophylaxis of the syndromes mentioned are those compounds which only have a slight effect on the blood sugar level.
The dosage of compounds of formula I or a physiologically tolerable salt thereof depends, as is customary, on the circumstances of the respective individual case, and is adjusted by the person skilled in the art according to the customary rules and procedures. It depends, for example, on the compound of formula I administered, its potency and duration of action, on the nature and severity of the individual syndrome, on the sex, age, weight, and the individual responsiveness of the human or animal to be treated, on whether treatment is acute or prophylactic, or whether, in addition to compounds of formula I, further active compounds are administered. Normally, in the case of administration to an adult weighing about 75 kg, a dose is needed which is about 0.1 mg to about 100 mg per kg per day, preferably about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight). The daily dose can be administered in the form of an oral or parenteral individual dose or can be divided into several, for example two, three, or four, individual doses. The administration can also be carried out continuously. In particular, if acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration, for example by injection or by intravenous continuous infusion, can be advantageous. A preferred dose range in critical situations is then about 1 mg to about 100 mg per kg of body weight per day. If appropriate, depending on individual behavior, it may be necessary to deviate upwards or downwards from the doses indicated.
Apart from as a pharmaceutical active compound in human medicine and veterinary medicine, compounds of formula I can also be employed, for example, as auxiliaries for biochemical investigations or as a scientific tool if a respective effect on ion channels is intended, or for the isolation or characterization of potassium channels. They can furthermore be used for diagnostic purposes, for example in in-vitro diagnoses of cell samples or tissue samples. Compounds of formula I or a salt thereof can further be used as chemical intermediates, for example for the preparation of further pharmaceutical active compounds.
A subject of the present invention are also certain cinnamoylaminoalkyl-substituted benzenesulfonylureas per se which are excluded by the disclaimer from the above-defined compounds of formula I which are per se a subject of the present invention, but which are not specifically disclosed in the prior art and which are a selection from compounds disclosed in general form in the prior art. These are compounds of formula If 
in which:
Y(f) is xe2x80x94(CR(5f)2)n(f)xe2x80x94;
the residues A(1f), A(2f), and A(3f), which are independent of one another and can be identical or different, are hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, formyl, or trifluoromethyl;
R(1f) is xe2x80x94Oxe2x80x94(C1-C4)-alkyl;
R(2f) is (C2-C6)-alkyl or (C5-C7)-cycloalkyl; the residues R(3f) and R(4f), which are independent of one another and can be identical or different, are hydrogen or (C1-C4)-alkyl;
the residues R(5f), which are independent of one another and can be identical or different, are hydrogen or (C1-C3)-alkyl;
n(f) is 1, 2, 3, or 4;
in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Like compounds of formula I, compounds of formula If also inhibitxe2x80x94as already explained abovexe2x80x94ATP-sensitive potassium channels, in particular in the heart, and are able to reduce or repair a dysfunction of the autonomic nervous system or a hypofunction or dysfunction of the vagal nervous system, in particular in the heart. All above details of compounds of formula I apply correspondingly to compounds of formula If. In compounds of formula If, Y(f) is preferably the residue xe2x80x94CH2xe2x80x94CH2xe2x80x94. The residues A(1), A(2f), and A(3f), which are independent of one another and can be identical or different, are preferably hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, or trifluoromethyl, in particular hydrogen, methyl, chlorine, fluorine, methoxy, ethoxy, or trifluoromethyl. The further statements with respect to preferred meanings of the residues A(1), A(2), and A(3) given above apply correspondingly to A(1f), A(2f), and A(3f). R(1f) is preferably methoxy or ethoxy, in particular methoxy. R(2f) is preferably (C2-C3)-alkyl or cyclohexyl, in particular ethyl, isopropyl, or cyclohexyl. R(3f) and R(4f) are preferably hydrogen. The present invention also relates to compounds of formula If or a physiologically tolerable salt or prodrug thereof for use as pharmaceuticals, and also pharmaceutical preparations which contain an efficacious amount of at least one compound of formula If and/or a physiologically tolerable salt and/or a prodrug thereof and a pharmaceutically tolerable carrier. Again, the above statements apply correspondingly to these pharmaceutical preparations.
The invention is illustrated by the examples below, without being restricted to these.